Scleroderma (SSc) is a devastating systemic disease in which lung involvement, largely from SSc-related interstitial lung disease (SSc-ILD), has emerged as the leading cause of overall mortality. Developing effective treatments for SSc-ILD will directly impact on both the quality and longevity of life. The original Scleroderma Lung Study (SLS I) was the first randomized controlled trial to demonstrate that SSc-ILD responds to a one year treatment with oral cyclophosphamide (CYC) with improvements in pulmonary function, dyspnea, skin disease, and health-related quality of life (HRQoL). However, the beneficial effects of CYC wane by the end of the 2nd yr, after completing one yr of therapy. Moreover, CYC was associated with significant acute toxicity, and longer therapy is limited by the risk for secondary malignancies. Mycophenolate mofetil (MMF), an immunosuppressive drug approved for organ transplantation, has been administered for up to 2 yrs to patients with SSc-ILD in several uncontrolled pilot studies. MMF was reported to be effective and safe. We hypothesize that the ability to administer MMF for two yrs will result in a better and more sustained improvement in SSc-ILD than can be achieved with one yr of CYC, and with less toxicity. To test this hypothesis, we propose a 5-yr, multi-center (12 clinical centers plus a Data Coordinating Center), parallel-group, double-blind, randomized controlled clinical trial comparing a 2-yr treatment with oral MMF (up to 1.5 g bid, as tolerated) with a 1-yr treatment with oral CYC (2 mg/kg/d for 1 yr followed by placebo MMF for a second yr to maintain the blind) in 150 patients with active SSc-ILD. Three SPECIFIC AIMS are proposed: 1) to determine whether MMF is more effective than CYC over the 2nd yr of a 24-mo period with respect to forced vital capacity as the PRIMARY OUTCOME and overall toxicity; 2) to compare MMF and CYC on the course of total lung capacity, single breath diffusing capacity for carbon monoxide, breathlessness (Mahler Transition Dyspnea Index), several HRQoL measures (SGRQ, SF-36), functional ability (Scleroderma Health Assessment Questionnaire) and skin thickness (modified Rodnam skin scores) as SECONDARY OUTCOMES; and 3) to advance our understanding of the biology and response to treatment of SSc-ILD through the collection and innovative analysis of blood samples and skin biopsies collected serially over time from study participants, the prospective validation of a combined outcome measure of overall treatment effect, and the assessment of the clinical utility (a patient-determined value measure) of treatments with MMF or CYC. (End of Abstract)